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Scientists in Cambridge and London have developed a DNA mutation fingerprint catalog that could help doctors identify who is responsible for a patient's tumor environment, including some of the fingerprints left in a patient's body. lung tumors by specific chemicals contained in tobacco smoke.
Our DNA, the human genome, includes a chain of molecules called nucleotides. These are represented by the letters A, C, G and T. Sometimes, changes occur in the spelling of our DNA – an A becomes a G, for example. These changes, called mutations, can be caused by a number of factors, some environmental, such as exposure to tobacco smoke or ultraviolet light.
As the cells divide and multiply, they copy their DNA to reproduce the spelling mistakes. Over time, the number of errors accumulates, resulting in uncontrolled cell growth – the development of tumors.
Previously, scientists had only a limited number of tools to determine the cause of an individual's tumor. Since it is now possible to study the human genome as a whole very quickly, scientists have been able to detect all the mutations in a patient's cancer and see patterns – or "mutational signatures." "- in these tumors.
Now, in a study published in the journal Cell, a team of researchers from Cambridge University and King's College London have developed a comprehensive catalog of mutation signatures caused by 41 environmental agents related to cancer. In the future, they hope to expand it further, using similar experimental techniques, to produce an encyclopedia of mutation patterns caused by environmental agents.
"Mutual signatures are the fingerprints left by carcinogens on our DNA, each of which is unique," says Dr. Serena Nik-Zainal, of the research unit of the Department of Medical Genetics and Disease. of CRM cancer from the University of Cambridge. Cambridge team. "They allow us to treat tumors as a crime scene and, as forensic scientists, allow us to identify the culprit – and his accomplices – responsible for the tumor."
The researchers exposed induced pluripotent stem cells – cutaneous cells that were reprogrammed to return to their "master" origin – to 79 known or presumed carcinogenic substances in the environment. The team then used whole genome sequencing to examine changes in agents' changes and found that 41 of the suspects had left a distinctive fingerprint on stem cell DNA.
"We have used this technique to create the most comprehensive catalog to date of DNA damage produced by environmental agents throughout the human genome," says Professor David Phillips, who is responsible for The King & # 39; s College team in London. "This should allow us to examine a patient's tumor and identify some of the carcinogens to which he has been exposed that could have caused cancer."
Some of the environmental agents studied are known carcinogens, such as polycyclic hydrocarbons and sunlight. For the first time, researchers also investigated some of the individual chemicals found in tobacco smoke and identified those that cause signatures similar to those found in smoker's lung cancer.
They also identified the fingerprints left by common chemotherapy drugs, some dietary chemicals and some present in the exhaust gases of diesel engines. This study shows how vulnerable human DNA is to many agents in our environment.
Dr. Nik-Zainal illustrates the potential uses of the catalog by citing the case of endemic nephropathy of the Balkans (BEN), linked to dietary exposure to a plant chemical called aristolochic acid. The mutational signature of this chemical was verified in this study to be virtually identical to the signature found in tumors of BEN patients. Thus, although this connection was made for the first time before this study, Dr. Nik-Zainal explains that this is an example of how their catalog could be used in the future.
"Our reference library will allow doctors in the future to identify the culprits responsible for cancer," adds Dr. Nik-Zainal. "Such information could be of invaluable help in helping to inform measures to reduce people's exposure to potentially dangerous carcinogens."
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The research was funded by a Wellcome Strategic Award, with additional support from Cancer Research UK and the Medical Research Council.
Reference
Kucab, JE and Zou, X et al. A collection of mutational signatures of environmental agents. Cell; May 2, 2019; DOI: 10.1016 / j.cell.2019.03.001
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